1. Field of the Invention
The present invention relates generally to the field of molecular biology. More specifically, the present invention relates to the cloning and characterization of a murine and human gene that encodes a novel protein with homology to the IL-17 receptor.
2. Description of the Related Art
Retroviral insertional mutagenesis in BXH2 and AKXD recombinant inbred (RI) mice induces a high incidence of myeloid leukemia and the proviral integration sites in the leukemias provide powerful genetic tags for disease gene identification (Bedigian et al., 1984; Gilbert et al., 1993). During the past several years, a number of disease genes have been identified in these leukemias by proviral tagging. These disease genes include a tumor suppressor gene, neurofibromatosis type I (Nf1); a gene with homology to the lymphoid-restricted type II membrane protein Jaw1, Mrv integration site 1 (Mrvi1); a gene encoding a hematopoietic cell growth and differentiation factor, myeloblastosis oncogene (Myb); three homeobox genes, homeobox A7 (Hoxa7), homeobox A9 (Hoxa9), and myeloid ecotropic viral integration site 1 (Meis1); a zinc-finger protein (Evi1); and a gene with homology to the ubiquitin-specific protease 8 (Usp8) oncogene and to genes encoding various cell cycle regulatory proteins, ecotropic viral integration site 5 (Evi5) (Buchberg et al., 1990, Viskochil et al., 1990, Shaughnessy et al., 1999; Copeland and Jenkins, 1999, Nakamura et al., 1996a, Morishita et al., 1988, Liao, et al., 1997). Four of the genes are proven or suspected human disease genes: EVI1, NF1 and HOXA9 are causally associated with myeloid leukemia and EVI5 with stage 4S neuroblastoma (Ogawa et al., 1996, Copeland and Jenkins, 1999, Nakamura et al., 1996b, Roberts et al. 1998), validating the usefulness of this approach for human disease gene identification.
Although proviral tagging has identified many disease genes, it is apparent that several more genes remain to be cloned. This is suggested by the fact only 45% of BXH2 leukemias contain a virally induced mutation in one of the genes identified so far. Disease genes for 55% of BXH2 leukemias remain to be identified. The same is true for human acute myeloid leukemias (AMLs) where the 11 different chromosomal translocations and inversions cloned to date are found in only 45% of acute myeloid leukemias (Look, 1997). Disease genes for 55% of acute myeloid leukemias remain to be identified. Ultimately, it should be possible to use proviral tagging to do a saturation screen for BXH2 disease genes. The expectation is that some of these genes will represent human acute myeloid leukemias genes that are not easy to clone because they are infrequently involved in human disease or are not marked by a cytologically detectable rearrangement. Given the large number of genes that may remain to be identified, this task could be difficult using conventional proviral tagging approaches, which rely on cloning leukemia-specific proviral integration sites into bacteriophage lambda.
With this potential problem in mind, an inverse PCR (IPCR) method for proviral tagging was developed that makes use of automated DNA sequencing and the genetic tools provided by the Mouse Genome Project, which greatly increases the throughput of proviral tagging for disease gene identification. More than 400 proviral integration sites from BXH2 myeloid leukemias (and AKXD T- and B-cell leukemias) were cloned and characterized using this inverse PCR method (Li et al., 1999), which lead to the identification of more than 90 new candidate leukemia disease genes (Li et al., 1999). Nineteen new common integration sites (sites that are targets of viral integration in more than one leukemia) were also identified in these studies and BLAST search and/or chromosome mapping identified candidate disease genes for 12 of these common sites (Li et al., 1999).
One common integration site identified by the inverse PCR is Evi27 (Li et al., 1999). While BLAST searches did not identify a candidate disease gene for Evi27, chromosome mapping studies showed that Evi27 maps to mouse chromosome 14 in a region of human 3p21 homology (Copeland et al., 1993). This result is interesting because treatment-related 3p21 breaks are often observed in myelodysplastic syndrome (MDS) and AML patients (Shi et al., 1996) and 3p21 is the most frequently deleted region seen in chronic myeloid leukemia (CML) (Johansson et al., 1997). Evi27 may be, therefore, an important human disease gene.
The prior art is deficient in lack of the characterization a novel cytokine receptor-related gene whose expression is upregulated by viral integration at Evi27. The present invention fulfills this long-standing need and desire in the art.